In female mammals, one of the two X-chromosomes is transcriptionally silenced through an epigenetic process known as X-chromosome inactivation (XCI). This dosage compensation mechanism ensures equal X-linked gene expression between XX females and XY males, and is necessary for normal development. A large body of experimental observations over the past several decades has implicated a role for XCI mis-regulation in the development and pathogenesis of various cancers, particularly female breast and reproductive cancers. First, loss of the Barr body -- a cytological signature of an inactivated X-chromosome -- has often been described for many female tumors. Second, X-chromosome anomalies, most often characterized by the gain of one or more transcriptionally active X-chromosomes and/or reactivation of the inactive X is a common phenomenon observed in many tumor cells. Third, the tumor suppressor, BRCA1, implicated in familial breast and ovarian cancers, has a role in X-chromosome inactivation. The objective of the proposed study is to investigate the role of X-chromosome reactivation in breast tumorigenesis. The long-term goal is to elucidate the role of X-linked genes in tumor development and pathogenesis.
The specific aims are: 1) to determine the role of ectopic X-linked expression in breast tumorigenesis using a mouse model system;2) to identify and characterize X-linked genes overexpressed in breast tumors.
| Zhang, Li-Feng; Huynh, Khanh D; Lee, Jeannie T (2007) Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing. Cell 129:693-706 |
